LECTURES

Based on the data available in the literature, the author has first systematized in detail the main stages of the design and clinical introduction of serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. Theoretical prerequisites for their emergence are described. The evaluation of the efficiency of depression therapy with drugs of this group in clinical trials and post-marketing studies is analyzed in the historical context. The reasons for temporary restrictions on their wide use are considered. There are data on the design of novel representatives of SNRI antidepressants.

The paper is devoted to the most common variant of cerebral small-vessel disease Р sporadic cerebral non-amyloid microangiopathy (SCNAMA) in the context of acute and chronic cerebral circulatory disorders. It highlights the topical issues of neuropathology and pathogenesis of the disease. The paper presents the current neuroimaging markers of SCNAMA with a detailed discussion of lacunar infarcts, cerebral microinfarctions, and microbleeds. It considers the clinical manifestations of the chronic form of the disease, including cognitive impairment. The problem in the differential diagnosis of SCNAMA and cerebral amyloid angiopathy is highlighted. The current possibilities of minimizing risks and improving the efficiency of treatment in this category of patients are discussed.

ORIGINAL INVESTIGATIONS

Daytime sleepiness is one of the clinically significant non-motor manifestations of Parkinson's disease (PD). One of its insufficiently studied aspects is a relationship between daytime sleepiness and nighttime sleep disorders.

Objective: to clarify the clinical characteristics of PD in patients with different types of daytime sleepiness and to estimate of the ratio of daytime sleepiness to clinical and polysomnographic characteristics of nighttime sleep in patients with advanced stages of PD.

Patients and methods. The investigation included 110 patients (56 men and 54 women) (mean age, 63.78+0.6 years) with PD (Hoehn and Yahr stage 2.6+0.2; disease duration, 6.3+3.2 years) without dementia. All the patients received therapy with levodopa at a mean daily dose of 667.8 mg; 98 of them had the drug in combination with dopamine receptor agonists at a stable dose. The unified PD rating scale, the PD sleep scale (PDSS), and the Epworth sleepiness scale (ESS) were applied. Nocturnal polysomnography (PSG) and the multiple sleep latency test (MSLT) were performed.

Results and discussion. There was daytime sleepiness in 44% of the patients: permanent sleepiness in 15%, sudden daytime sleep attacks (along with low daytime sleepiness (ESS) in 14%, and permanent drowsiness concurrent with sleep attacks in 15%. The PSG findings showed a decrease in sleep efficiency, an increase in the duration of the first stage of sleep, a reduction in the duration of the second and third sleep stages, an extension of rapid eye movement (REM) sleep latency, and frequent awakenings (sleep fragmentation). PSG also demonstrated REM sleep behavior disorders (RBD) in half of the examinees.

Patients with sleep attacks differed from those with permanent drowsiness without sleep attacks with more severe sleep disorders (PDSS) and shorter sleep latency (MSLT). Patients with the RBD phenomenon had shorter sleep latency (MTLS) than those without this parasomnia. Patients with moderate or severe sleepiness (ESS scores of >10) differed from those with milder drowsiness (ESS scores of 410) and a lower representation of the third sleep stage.

Conclusion. There is evidence for the association of daytime sleepiness in PD with reduced efficiency, changes in the nighttime sleep pattern, and RBD.

What factors negatively influence the accuracy of topical diagnosis of spinal nerve root lesion during neurological examination has not been solved until now.

Objective: to identify the nature of the relationship between the accuracy of topical diagnosis of spinal nerve lesion from neurological symptoms in patients with cervical disk herniation and the peculiarities of their emotional status and quality of life.

Patients and methods. Forty-eight patients with cervical disc herniation were examined. At first, the level of spinal nerve root lesion established during neurological examination was compared with the results of magnetic resonance imaging or computed tomography and surgical intervention. Thereafter, the importance of emotional factors in determining the accuracy of topical diagnosis is studied in these patients.

Results and discussion. If there was a divergence between preliminary neurological and final diagnoses, personality traits, such as hysteria, psy-chasthenia, alexithymia, and trait anxiety were most significant. The most substantial differences were found in the index of alexithymia. The accuracy of topical diagnosis was influenced not only by the psychological profile of patients with cervical disc herniation, but also by their qualty-of-life indicators. These are persons who are anxious and suspicious and are characterized by anxiety, fearfulness, indecision, and constant doubt. They use the symptoms of a somatic disease as a means to avoid responsibility. These patients solve all their problems, by escaping into disease, which causes social maladjustment.

Conclusion. The features of an individual's psychological profile as increased anxiety, hysteria, and psychasthenia reduce the accuracy of topical diagnosis of the lesion by 25.6%. Patients with cervical disk herniation, low quality-of-life indicators, and high scale scores for hypochondria, depression, psychasthenia, and trait anxiety need their emotional status to be corrected.

Objective: to develop a Russian version of the modified Rankin Scale (mRS) and to assess its psychometric properties.

Patients and methods. The investigation involved 50 patients (25 women, 25 men) over 18 years of age (mean age, 56 years) with an acute cerebrovascular accident diagnosis. During the validation procedure, the authors carried out the linguocultural ratification of mRS, prepared its Russian-language version, and then assessed its psychometric properties (reliability, sensitivity, validity).

Results and discussion. Translation and linguistic adaptation of mRS was successfully completed. The results obtained in assessing the psychometric properties of the developed Russian version of the scale reflect its high reliability and the valid and reliable indicators of its sensitivity. A statistical study of constructive and content validity also determined the high significance of differences.

Conclusion. The investigation has resulted in the official Russian version of mRS, which is recommended for use by neurologists and rehabilitation specialists in both daily clinical practice and in clinical trials.

Patients with somatoform disorders (SD) seek specialized psychiatric care late. Although many factors that prevent the timely visits by patients with SD for specialized psychiatric care are known, this problem requires further study.

Objective: to analyze the role of information sources and iatrogenic factors in unreasonably selecting a specialist by patients with SD to visit him/her for primary medical advice.

Patients and methods. Sixty-six women aged 19 to 40 years with new-onset SD (F 45.0) were examined. Two patient groups were identified: a study group of 41 patients (mean age, 31.5+1.2years) and a comparison group of 25 (mean age, 31.6+0.8years) (p>0.5). Primary care physicians had examined and treated the study group patients long (for 1 to 6 years) before their visit to a psychiatrist. The comparison group patients had been seen by a psychiatrist just in the first year of the disease.

Anamnestic, clinical, andpsychopathological methods were used when examining the patients.

Results and discussion. For their first visit, the patients with SD had selected a therapist and a neurologist more frequently and a cardiologist and an endocrinologist somewhat less frequently. This selection was also affected by the specialists' high titles, psychiatric consultation-avoiding behavior, and conversion mechanisms. Acquaintances' advice and Internet information as health information sources contribute to the unjustified revisits by these patients to primary medical specialists for a long time. Iatrogenic mechanisms were found to play a role in forming a false concept of a disease and destructive behavioral strategies leading to the chronization and progression of SD. Patients with SD who are long and ineffectively exposed to numerous diagnostic procedures and ineffective treatment in the primary health care need psychiatric counseling and psychotherapeutic support.

Conclusion. The diagnosis of SD remains ineffective in an outpatient setting. There is a need for an educational program on SD within the continuing health education system.

Age-related cognitive changes in the Russian population have not been sufficiently studied.

Objective: to assess the time course of changes in cognitive functions (CF) in two serial measurements 9 years apart in the urban population of middle, elder, and senile age and their relationship to education level.

Patients and methods. A random male and female sample of45-69-year-old Novosibirsk residents (n=9360; HAPIEE project) was surveyed. CF was tested by standard methods. Resurvey was conducted in a random subsample (n=1663) included in this analysis. The mean follow-up period was 8.8 years (SD 1.1).

Results and discussion. The test for semantic verbal fluency revealed its dynamic decline in all age groups, which was steeper in women than in men (p<0.001). Persons aged 70 years and older showed negative changes in memory, verbal fluency, and attention (p<0.001). Persons with primary (6%) and vocational (26%) education had steeper rates of decline in delayed recall (p=0.011; 0.038) than those with university education (35%).

Conclusion. It is established that a dynamic decrease in CF begins at the age of55—59years; it is steeper among those aged 70 years and older. An age-related decline in memory function is accelerated in persons with lower educational levels.

Multiple sclerosis (MS) is a chronic dysimmune neurodegenerative disease of the central nervous system, the risk of which depends on genetic and environmental factors. The Altai Territory of the Russian Federation shows an increase in the prevalence of MS from 15.5 cases per 100,000population in 1984 to 56.1 in 2017.

Objective: to identify potential environmental risk factors for MS in the Altai Territory.

Patients and methods. A one-stage randomized study using the method of analytical epidemiology covered 200patients with MS and 200 volunteers without this condition, the representatives of European ethnicity, who were born and lived in the Altai Territory. The investigators surveyed the patients, analyzed their medical records, and assessed the relationship of the prevalence of MS to the characteristics of the territories of residence.

Results and discussion. The prevalence of MS was 1.8 times higher in cities and towns than in villages (p=0.003), in areas with heavy metal (lead and molybdenum) ore deposits, chemical and oil refineries located within a 5-km radius from the place of residence. The risk of MS is unassociated with measles, rubella, chicken pox, mumps, whooping cough, herpes infection, chronic nasopharyngeal bacterial infections, diabetes mellitus, allergic status, and contact with household, agricultural, metal, and medicinal poisons, organic solvents, and oil products.

Conclusion. The identified environmental risk factors can serve as a basis for recommendations for the prevention of MS in persons at high genetic risk for this disease.

Up to 15% of patients with secondary brain tumors of unknown primary are admitted to a neurosurgery department. Identification of a primary tumor site on the basis of surgical material immunophenotyping in routine clinical practice has a significant potential; however, this requires systematization.

Results and discussion. A study using the IHC panel made it possible to obtain the following tumor phenotypes in the patients: CK5/6+, p63+, CK7+, UPIII+ (urothelial cancer) (n=3); CK5/6-, CK7+, TTF-1+, CDX2- (lung adenocarcinoma) (n=2); CK5/6+, p63+, CK7-, UPIII, TTF-1- (squamous cell carcinoma) (n=1), and CK5/6-, CK7+, TTF-1-, CDX2-, Her2/neu+ (breast cancer) (n=1). Evidence of the primary focus of the tumors was subsequently confirmed by instrumental techniques in all cases when cancer of the breast, lung and urinary system was directly sought. The findings were used to elaborate an algorithm for the differential diagnostic immunophenotyping of brain metastases.

Conclusion. The primary focus of brain carcinoma was detected in all cases on the proposed IHC panel. The systematized algorithm for differential diagnostic immunophenotyping can be used in clinical practice.

Motor and non-motor symptoms are identified in the clinical picture of Parkinson's disease (PD). Among its non-motor manifestations, cognitive impairment (CI) and emotional disorders play a special role in PD. It is important to search for new forms and methods of cognitive therapy in patients with PD.

Objective: to analyze neuropsychological status and quality of life (QOL) in PD patients and to evaluate the efficiency of personalized combination therapy with a stimulating cognitive motor training on computer and mobile devices in these patients.

Patients and methods. The investigation enrolled 112 patients with PD. A study group included 56 PD patients who received a cycle of combination therapy with cognitive-motor training on PC and mobile devices; a control group consisted of 56 PD patients who had only a drug therapy cycle. To evaluate neuropsychological status and QOL, the investigators used the Montreal Cognitive Assessment (MoCA), the McNair and Kahn memory self-evaluation scale, the Hospital Anxiety and Depression Scale (HADS), and the 36-Item Short Form Health Survey (SF-36) questionnaire.

Results and discussion. According to MoCA scores, CI of varying severity was diagnosed in the majority of patients: in 75 and 80.4% in the study and control groups, respectively. Depressive syndrome was detected in 53.6 and 64.3% in these groups, respectively. According to the SF-36, the physical status of patients had the greatest effect in reducing their QOL. There were treatment-induced statistically significant positive changes for the following domains: physical functioning (p<0.01), role-physical functioning (p<0.001), pain intensity (p<0.01), general health (p<0.01), role emotional (p<0.0001), and mental health (p<0.01).

Conclusion. The investigation has shown the efficiency of personalized therapy including stimulating cognitive-motor training on computer and mobile devices, which improves neuropsychological status and QOL in patients with PD.

Muscle relaxants are used in the treatment of musculoskeletal pain. The exact molecular mechanisms of action of muscle relaxants are not always clear. Some muscle relaxants show mainly an anticholinergic effect, others have GABAergic one; they differ in accumulation in muscles, central nervous system, and other tissues.

Objective: to carry out a comparative chemoreactome analysis of tolperisone with tizanidine and baclofen, allowing the pharmacological action of each of the molecules to be specified.

Material and methods. The investigators applied a chemoinformational approach, i.e. compared the chemical structure of the studied molecules with the structures of millions of other molecules, for which the molecular and pharmacological properties are known. The analysis is based on the latest machine learning technologies developed within the framework of the theory of combinatorial solvability analysis, the theory of topological and metric approaches to analyzing the features of the so-called big data.

Results and discussion. Tolperisone was most likely to accumulate in the skeletal muscles, adrenal cortex, and hypothalamus. The drug caused a muscle relaxant effect through cholinergic action, practically without affecting adrenergic, dopaminergic, GABAergic neurotransmission. Each of the studied molecules was established to exert dose-dependent antispasmodic and analgesic effects. Tolperisone was shown to have antithrombotic and antiinflammatory effects due to inhibition of the activity of tumor necrosis factor-a and to modulation of the metabolism ofprostaglandins and leukotrienes.

Conclusion. Significant differences were found in the mechanisms of molecular action of tolperisone, tizanidine, and baclofen, which was responsible for differences in the time of onset and duration of action of a muscle relaxant, in the action on CNS or peripheral nervous system neurons, as well as in additionalpleiotropic effects and adverse reactions.

Objective: to investigate the effectiveness of cognitive and motor training as an additional method to basic therapy in patients with Alzheimer's disease (AD) and vascular cognitive impairment (VCI).

Patients and methods. The investigation enrolled 41 patients (15 women and 26 men; mean age. 73.59+6.3 years), including 32 patients with AD (mean age 74.94+5.15 years) and 9 patients with VCI (mean age, 72.31+4.98 years). Cognitive impairment (CI) corresponded to mild dementia in 15patients (5 women and 10 men; mean age 74.6+2.8years) and to moderate dementia in 29 (10 women and 19 men; mean age 72.1+3.2 years). The patients were randomly assigned to individual, group, and mixed (individual and then group) cognitive training groups. Quantitative scales were used to assess changes in CI and emotional and behavioral disorders after 1.5, 3, and 6 months of therapy.

Results and discussion. During cognitive and motor training, all the groups showed a significant decrease in the severity of CI (p < 0.05), depression, anxiety, and apathy. The effectiveness of the training was further influenced by the severity of concomitant cardiovascular disease, the degree of apathy, adherence to the training, and the early initiation of basic symptomatic therapy.

The greatest positive changes in anxiety and depressive disorders were noted in the patients receiving group cognitive and motor training.

Conclusion. The results of the investigation allow group cognitive and motor training to be recommended as a mainstay in the therapy of patients with CI concurrent with emotional disorders.

Schizophrenia is a socially significant mental disorder characterized by early onset and high time and financial expenditure on treatment. The basic drugs in these patients are antipsychotics that are highly effective against the positive and negative symptoms of schizophrenia, but at the same time have a wide range of adverse reactions (ARs). The clinical effect and tolerability of antipsychotics are variable and depend on the characteristics of genetically determined mechanisms (transportation, biotransformation, and elimination).

The paper describes a clinical case of a female patient with schizophrenia who has been noted to be unresponsive to antipsychotic therapy for some years after the onset of the disease. After pharmacogenetic testing, she was found to be homozygous for the nonfunctional allelic variant CYP2D6*4 (1934 G>A, rs3892097), which was the reason for the complete shutdown of isoenzyme 2D6 activity and the development of ARs in the use of initial doses of antipsychotic drugs, as well as for an increase in the severity of ARs with aggravation of psycho-producing symptoms with an even slow titration of the daily dose.

REVIEWS

The recently discovered glymphatic system (GS) ensures the efficient clearance of interstitial fluid and soluble compounds from the central nervous system into cerebrospinal fluid (CSF), which compensates for the lack of conventional lymphatic vessels in the brain parenchyma. This unique anatomical and physiological phenomenon had been unknown until 2012. GS lacks inherent proper vessels Р the current of CSF and interstitial fluid is carried out directly inside the arterial walls (the perivascular pathway) or near the walls of the cerebral arteries and veins (the paravascular pathway). Current biorheological technologies could establish a special role of aquaporin-4 in the filtration of CSF and interstitial fluid. The close link between GS and the CSF circulatory system allows the established views on fluid dynamics within the brain to be reconsidered. The discovery of GS can contribute to our understanding of the pathogenesis of increased intracranial pressure and neurodegenerative diseases, as well as to the elaboration of new therapeutic approaches to their treatment.

This review provides information on prospects for using the antidepressant agomelatine in neurological practice. The drug has a unique receptor profile, being a melatonin receptor type 1 and 2 agonist and a serotonin receptor subtype 2C antagonist. Due to this and in addition to antidepressant action, the drug has a number of other effects, such as analgesic, anti-apathetic, anti-asthenic, procognitive, anxiolytic, and sleep-normalizing ones, which are of great importance in the treatment of neurological diseases. There are clinical and experimental data that prove the high efficiency and safety of agomelatin in the follow-up of patients with post-stroke depression, Parkinson’s disease, Alzheimer’s disease, Pick’s disease, Huntington’s disease, chronic fatigue syndrome, and pain syndromes.

Facial agnosia (prosopagnosia) is one of the causes of limitations in the life of patients with focal vascular, inflammatory, traumatic, and tumor lesions of the brain; however, the clinical significance of these lesions in neurological practice is often underestimated.

The review briefly presents the current understanding of the neurophysiological basis of facial gnosis and its neuroanatomic correlates. It discusses the clinical variants of prosopagnosia, the features of neuropsychological diagnosis, and adopted approaches to patient rehabilitation. It also highlights the importance of developing standardized methods for facial agnosia to improve the detection of prosopagnosia in focal brain lesions.

The brain is a natural target organ in hypertension and, as shown by some clinical observations, it is affected earlier than other organs and systems. Due to the specific features of the anatomy of cerebral circulation, hypertensive microangiopathy leads primarily to damage to the subcortical basal ganglia and deep white matter. Clinically, this is manifested by a concurrence of predominantly subcortical cognitive impairment and emotional and behavioral disorders as depression, emotional lability, and apathy. Some features of depression, such as the prevalence of anhedonia and fatigue and the significant severity of cognitive and somatic symptoms in an elderly person with vascular disease, suggest its organic nature (vascular depression).

Information about a favorable prognosis for a patient, recommendations for activities, and optimal pharmacotherapy are a mainstay in the effective treatment of acute nonspecific low back pain (NLBP). Standard pharmacotherapy for acute NLBP includes nonsteroidal anti-inflammatory drugs (NSAIDs). However, the longer their administration and larger doses, the higher the risk of side effects are. NSAIDs are contraindicated in some cases. In this connection, it has become necessary to search for new opportunities for the pharmacotherapy of acute NLBP. The results of experimental studies have demonstrated the analgesic and anti-inflammatory effects of high-dose B vitamins. Clinical trials have confirmed the efficacy of vitamin B complex (thiamine, pyridoxine, and cyanocobalamin) in the treatment of acute NLBP. The paper considers the practical significance of concomitant administration of B vitamins and NSAIDs in NLBP and notes the efficacy of milgamma used both alone and in combination with NSAIDs in the treatment of acute NLBP.

The paper gives comparative data on the efficacy and tolerability of valproic acid (VA, valproate) and carbamazepine (CBZ) for different types of epilepsy and seizures in different age and clinical groups. The results of studies suggest that despite a more than 50-year history of their effective use, the extended-release formulations of VA and CBZ remain the drugs of first choice for many types of epilepsy.

CBZ is effective for focal epilepsy and isolated generalized tonic-clonic seizures. However, its use is substantially limited by properties, such as cytochrome P450 induction and autoinduction, high drug-drug interactions, the aggravation of absences, negative myoclonus, myoclonic and atonic seizures, an effect on the profile of steroid sex hormones, elevated concentrations of atherogenic lipids and cholesterol, myocardial conduction disorders, and hyponatremia.

Due to the multiple mechanism of action, VA is prescribed for almost all types of epilepsy and seizures in patients of different ages. VA should not be used (if the clinical situation allows) in women of childbearing age, in some infantile epileptic encephalopathy, inherited metabolic diseases, and chromosomal abnormalities. Effectiveness against different types of seizures and epilepsy, good tolerability, minimal aggravation risk, high retention rate of monotherapy, the presence of a variety of dosage forms, and favorable pharmacokinetic and pharmacodynamic profiles still make VA essential in many clinical situations.

The paper presents the proceedings of the Round Table with the participation of leading neurologists, which is devoted to chronic cerebrovascular diseases. It is noted that chronic cerebral ischemia (CCI), or dyscirculatory encephalopathy (DEP), is one of the most common neurological diagnoses in our country. The pathogenesis, clinical presentations, diagnosis and treatment of CCI (DEP) and its matching with vascular cognitive impairment (CI), which is regarded in foreign literature as the main manifestation of chronic cerebrovascular disease (CVD) were considered. The authors analyze clinical trials evaluating the efficacy of vinpocetine (Cavinton) in chronic CVD, dizziness, CI, as well as the use of new vinpocetine formulations, such as Cavinton Comforte, in various neurological diseases, dysphagia in particular, in poststroke patients.

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